Hydroxyurea is a cell-cycle specific agent that blocks DNA synthesis by inhibiting ribonucleotide reductase, the enzyme that converts ribonucleotides to deoxyribonucleotides. Hydroxyurea has been shown to induce the production of fetal hemoglobin (HbF), initially in non-human primates, and now in patients with sickle cell anemia. The majority of patients with sickle cell disease respond to the drug with a more than two-fold increase in HbF levels; in some patients the percent of HbF exceeds 10 or 15 percent. We have found in our laboratories that hydroxyurea exerts many of its effects via the production of nitric oxide gas. In this study we treat patients chronically with hydroxyurea to determine hematological changes longitudinally. Once a maximal Hb-F raising effect of hydroxyurea has been established, oral L-arginine (the substrate for NO synthase) and sildenafil (Viagra?, a phosphodiesterase inhibitor that potentates cGMP dependent signaling) is added to determine the ability of other agents to enhance HbF synthesis, especially in hydroxyurea non-responders or partial-responders. We began enrolling patients in May 2003 and have treated 25 patients to date, 14 with hydroxyurea and L-arginine and 11 with hydroxyurea and sildenafil.